Fanconi anemia differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

Fanconi Anemia must be differentiated from Aplastic Anemia, Paraoxysomal Nocturnal Hemoglobinuria, and Chromosomal breakage syndrome and Hereditary Bone marrow failure syndrome (Dyskeratosis congenita and other short telomere syndromes).

Differentiating X from other Diseases

• Fanconi Anemia must be differentiated from other diseases that cause Pancytopenia, Congenital anomalies, and associated with malignancy such as Aplastic Anemia, Rare chromosomal breakage syndrome and inherited bone marrow failure.

• As Fanconi Anemia resembles with variety of other diseases that causes pancytopenia, must be differentiated on basis on congenital anomalies and chromosomal breakage test.
• In contrast fanconi anemia must be differentiated from other bone marrow failure that cause congenital anomalies, such as hereditary bone marrow failures.

Preferred Table

Clinical manifestations							Para-clinical findings							Gold standard	Additional findings
Symptoms				Physical examination
							Lab Findings			Imaging			Histopathology
Symptom 1		Symptom 2	Symptom 3	Physical exam 1	Physical exam 2	Physical exam 3	Lab 1	Lab 2	Lab 3	Imaging 1	Imaging 2	Imaging 3
Short stature, delicate features, upper limbs absent or hypoplastic thumbs, supernumerary, bifid clinodactyly	Fanconi Anemia	infection, petechia, pallor		Skin – Generalized hyperpigmentation; hypopigmented areas; large freckles, café-au-lait spots		Head – Microcephaly or hydrocephaly; birdlike face, mid-face hypoplasia, Sprengel's deformity of neck, Eyes- Microphthalmia, ptosis, epicanthal folds, strabismus	Complete blood count Peripheral blood smear   Reticulocyte count Complete metabolic panel Prothrombin time/partial  thromboplastin time (PT/PTT) Blood type and screen	Cytopenia, Bone marrow failure			Gastrointestinal anomalies – Atresias, imperforate anus, tracheoesophageal fistula, malrotation, Kidney – Abnormal, ectopic, horseshoe, hypoplastic, or absent kidney; hydronephrosis	Cardiopulmonary anomalies – Congenital heart disease (patent ductus arteriosus, atrial or ventricular septal defects, coarctation, situs inversus)		FA gene sequencing	Incrreased chromosomal breakage in response to mitomycin C or diepoxybutane (quite sensitive but not entirely specific)
recurrent infections due to neutropenia, mucosal hemorrhage or menorrhagia due to thrombocytopenia, or fatigue and cardiopulmonary findings associated with progressive anemia.	Acquired Aplastic Anemia	infections including bacterial and fungal in cases of severe neutropenia	Transient pancytopenia and bone marrow hypoplasia may be caused by a number of exposures including medications, chemicals, certain viral infections, and sepsis or other severe bacterial infections.	especially pallor and petechiae.	The liver, spleen, and lymph nodes are typically enlarged in AA, if its enlarged it may suggest alternative diagnosis.		Complete blood count Peripheral blood smear   Reticulocyte count Complete metabolic panel Prothrombin time/partial  thromboplastin time (PT/PTT) Blood type and screen	Serum chemistries, including electrolytes, liver function tests (including lactate dehydrogenase [LDH]), and renal function tests should be performed, Also serum B12 and Folate should be performed to exclude						Bone marrow aspiration and Biopsy= hypocellular bone marrow in the absence of an abnormal infiltrate or marrow fibrosis.	typically a more rapid onset and progression of cytopenias; and a response to immunosuppressive therapy
Fatigue ●Dyspnea ●Hemoglobinuria	Paroxysmal nocturnal hemoglobinuria (PNH)	Abdominal pain ●Bone marrow suppression ●Erectile dysfunction	Chest pain ●Thrombosis ●Renal insufficiency				Anemia ●Increased reticulocyte count ●Increased lactate dehydrogenase (LDH) and bilirubin ●Decreased haptoglobin ●Free serum hemoglobin with pink/red serum Bone Marrow: PNH usually have a normocellular or hypercellular bone marrow with erythroid hyperplasia. Stainable iron is often absent	hemolytic anemia (indirect hyperbiliribinemia)  Intravascular hemolysis in PNH can lead to ARF and CRD.	●Hypocellular, normocellular or hypercellular bone marrow, often with erythroid hyperplasia; erythroid dysplasia is not uncommon		●Findings of iron deficiency may be seen in some patients due to excessive iron loss from hemoglobinuria and hemosiderinuria (eg, low iron, low ferritin, increased transferrin, absent bone marrow iron	●Hemoglobinuria with pink/red urine, positive dipstick for heme, and negative sediment for red blood cells ●Negative direct antiglobulin (Coombs) test (DAT)	●Hypocellular, normocellular or hypercellular bone marrow, often with erythroid hyperplasia; erythroid dysplasia is not uncommon	FLAER: Flow cytometry detect (GPI) anchored proteins, which are reduced or absent on blood cells in PNH. Acquired mutations in the PIGA gene result in the dominance of a hematopoietic progenitor cell clone lacking glycosylphosphatidylinositol (GPI) anchors
	Other inherited bone marrow failure syndromes (Dyskeratosis congenita and other short telomere syndromes)	Bone marrow failure Classic mucocutaneous and additional dermatologic findings •Skin dyspigmentation •Nail irregularities •Leukoplakia •Premature graying/hair loss •Hyperhidrosis – 15 percent Ophthalmologic/Epiphora  (excessive tearing/lacrimal  duct stenosis) ●Neurologic/Cognitive •Developmental delay •Ataxia/cerebellar hypoplasia – approximately •Microcephaly	●Pulmonary disease (pulmonary fibrosis) ●Endocrine/Growth/Urologic  features •Short stature •Intrauterine growth retardation •Hypogonadism/Undescended  testes •Urethral stricture/phimosis  •Osteoporosis and related complications	Unlike Fanconi anemia, individuals with DC do not appear to have impaired fertility ●Dental manifestations (caries) ●Gastroenterologic/Hepatologic  manifestations •Esophageal strictures •Liver disease (cirrhosis, fibrosis) or gastroenteropathy ●Cancer			Reticular dysgenesis (RD) is a type of severe combined immunodeficiency caused by mutations in the AK2 gene that may also be associated with bone marrow aplasia, unlike FA, patients with RD develop bone marrow aplasia in infancy associated with sensorineural hearing loss and severe adaptive immune dysfunction								negative chromosomal breakage test.
Symptom 1	Diseases	Symptom 2	Symptom 3	Physical exam 1	Physical exam 2	Physical exam 3	Lab 1	Lab 2	Lab 3	Imaging 1	Imaging 2	Imaging 3	Histopathology	Gold standard	Additional findings
	Drug-induced or infection-associated pancytopenia
Like FA, these rare chromosomal instability syndromes are associated with multiple congenital anomalies, often including microcephaly, short stature, and increased risk of malignancy. Also like FA, t.	Rare chromosomal breakage syndromes, Nijmegen breakage syndrome (NBS), Bloom syndrome (BLM), ataxia telangiectasia (ATM), LIG4 syndrome (LIG4), NHEJ1 deficiency (NHEJ1), Seckel syndrome (ATR), and the cohesinopathies Roberts syndrome (ESCO2) and Warsaw breakage syndrome (DDX11).						compared to FA, these conditions show subtle differences in the associated congenital anomalies, the spectrum of associated malignancies, and the specific abnormalities seen within chromosomal breakage testing (eg, increased chromosome 7 and 14 abnormalities in NBS, railroading figures in cohesinopathies).							these syndromes will often cause an abnormal chromosomal breakage tes	patients with NBS do not typically exhibit bone marrow failure except in the setting of evolving malignancy.
MDS can arise de novo or secondary to another bone marrow disorder;	De novo myelodysplastic syndrome (MDS)	many patients with FA develop secondary MDS in child/young adults.					de novo MDS can cause bone marrow failure	variable cytopenias, multilineage dysplasia, cytogenetic abnormalities, and increased blasts					, individuals with MDS in whom FA is being considered should have chromosomal breakage tests performed on skin fibroblasts rather than hematopoietic cells, because bone marrow cytogenetic abnormalities associated with MDS clones may skew chromosomal breakage results performed on lymphocyte		Unlike FA or FA with secondary MDS, de novo MDS is not associated with congenital anomalies, an abnormal chromosome breakage test, or FA mutations